1. Field of the Invention
The present invention relates to a method for inhibiting euPTX3 to treat nasopharyngeal carcinoma (NPC) by an amino acid sequence, more particularly for inhibition of euPTX3 from promoting the migration and invasion of nasopharyngeal carcinoma cells, promoting angiogenesis and inhibiting macrophage phagocytosis to further treat nasopharyngeal carcinoma.
2. Description of Related Art
Many researches reported that acute inflammation increases the probabilities of normal cells to become tumorigenic and enhances the occurring rate of cancer cell migration and invasion. Tumor-associated macrophages (TAM) are the most abundant immune cells within the tumor stroma and are required for a number of functions important for tumor progression, such as promoting tumor cell proliferation, angiogenesis, incessant matrix turnover and repressing the adaptive immune responses. Clinical investigations have shown that high levels of macrophage infiltration into tumors are associated with a poor prognosis.
PTX3 is a long pentraxin protein, whose mechanism of action is under study. In osteoblasts, prostaglandin E2 (PGE2) increases the translocation of transcription factor CCAAT/enhancer binding protein delta (CEBPD) from cytoplasm to nucleus by activating protein kinase A to result in an increased expression of insulin-like growth factor (IGF-1). A high expression level of CEBPD in inflammation indicates that CEBPD and its downstream target proteins play important roles in inflammation. In astrocytes, an increase of CEBPD is able to activate PTX3 protein to suppress the phagocytosis of damaged cells by macrophage, in relation to age-associated disorder, e.g. Alzheimer's disease. As such, most of prior arts disclosed the relation of CEBPD to PTX3 associated mechanisms. Nasopharyngeal carcinoma represents a unique tumor microenvironment where the epithelial tumor cells are surrounded by abundant infiltrating immune cells. During tumorigenesis, tumors can adapt to evade immunosurveillance by altering the properties and functions of the host's stromal and/or immune cells.
The invention connects PTX3 to tumor-associated macrophages and nasopharyngeal carcinoma. It suggests that PTX3 has abilities of promoting the migration of nasopharyngeal carcinoma cells and angiogenesis, and abilities of inhibiting macrophage phagocytosis, whereas PTX3 antibody and recombinant PTX3 protein of prokaryotes can inhibit the function as described above. Thus, an amino acid sequence for treating nasopharyngeal carcinoma has been developed in view of this novel finding and convenience of application.
A plurality of amino acid sequences available in nature shares at least 85% sequence homology with SEQ ID NO:1. For example, the amino acid sequence of pentraxin of Otolemur garnettii (uncharacterized protein, H0WWH7) has sequence homology of 86% with the Seq. ID No: 1 in the present invention. The amino acid sequence of pentraxin of Callithrix jacchus (F7I850) shares 92.1% sequence homology with the Seq. ID No: 1 in the present invention. H2QNM9 has disclosed a sequence having sequence homology of 98.1% with Seq. ID No: 1 in the present invention while P26022 has disclosed a sequence sharing 100% sequence homology with Seq. ID No: 1 in the present invention. However, the function of the amino acid sequences mentioned above is not revealed.
U.S. Pat. No. 8,003,109 (Bottazzi, et al.) has revealed a kind of pharmaceutical composition comprising a long pentraxin PTX3 that shares 95% sequence homology with Seq. ID No: 1 in the present invention. The long pentraxin PTX3 is used to treat infectious and inflammatory diseases, or tumor diseases as disclosed in the abstract. However, after reviewing the specification in details, it is clear that the anticancer activity reported above correlates closely with the leukocyte recruitment which occurs in the mouse as a result of recognition of the C1q by PTX3. In genetically modified mice, no such leukocyte recruitment occurs. Thus the anticancer activity of this pharmaceutical composition is based on leukocyte recruitment. The capability of leukocyte recruitment of the pharmaceutical composition presents that the pharmaceutical composition can also be applied to treat diseases caused by pathogens (such as bacteria, fungi, protozoa, or virus). The anticancer activity of the amino acid sequence revealed by Bottazzi and having 95% sequence homology with Seq. ID No: 1 is provided after binding to the ligand—C1q and the binding of the amino acid sequence to the C1q results in leukocyte recruitment. However, Bottazzi hasn't discussed the effect of this amino acid sequence on migration and invasion of nasopharyngeal carcinoma cells, angiogenesis and macrophage phagocytosis.
The present invention provides an amino acid sequence for inhibiting euPTX3 from promoting the migration and invasion of nasopharyngeal carcinoma cells, promoting angiogenesis and inhibiting macrophage phagocytosis so as to treat nasopharyngeal carcinoma effectively. The amino acid sequence is derived from PTX3 of prokaryotes (E. coli), and having at least 95% sequence homology with SEQ ID NO:1 while the amino acid sequence of SEQ ID NO:1 is preferred. Generally, the amino acid sequence whose sequence homology with SEQ ID NO:1 is larger than 95% has the same capability as SEQ ID NO:1 of inhibiting nasopharyngeal carcinoma cells.